Project Summary/Abstract PGRMC1 is expressed in the human endometrium at highest levels during the estrogen dominated proliferative phase, suggesting that this relatively uncharacterized protein functions to coordinate epithelial cell proliferation. Our lab recently floxed the murine Pgrmc1 gene in an effort to evaluate the function of this gene in the context of female fertility. Conditional mutagenesis studies using Pgr-cre mice revealed that PGRMC1 is necessary for the expression of several growth factors and subsequent epithelial cell proliferation in response to estradiol (E2). IGF-1, for example, is well-established as a growth factor produced in the endometrial stromal compartment in response to E2 that in turn binds to its cognate receptor on epithelial cells and drives proliferation. Based on these novel findings, the central hypothesis of this application is that PGRMC1 is essential for E2-induced endometrial epithelial cell proliferation and over-expression of PGRMC1 elevates E2- induced proliferative responses in the endometrium. A likely and expected consequence of PGRMC1 over- expression is the elevated production of growth factors that would promote development and progression toward endometrial cancer. Indeed, epidemiological studies support the concept that high adult body mass index, which results in elevated systemic estrone, and postmenopausal hormone replacement therapy, particularly unopposed E2 taken for an extended period of time, are solid risk factors for Type 1 E2-dependent endometrial cancers. The goal of this application is to investigate the molecular mechanisms by which PGRMC1 functions in the regulation of E2 signal transduction and production of paracrine growth factors that promote endometrial proliferation. Identifying PGRMC1-interacting proteins is a central objective and this will help establish PGRMC1 mechanism of action. A fundamental understanding of how estradiol (E2) signals is necessary for advancing reproductive biology and for developing strategies to combat hyperproliferative diseases of the endometrium such as endometriosis and endometrial cancer.